Hyperlipidemia

Hyperlipidemiamoa

1. Jaineel Dharod, Dept. of Pharmacology Hy perlipidemia

2. Definitions Classification Mechanism of actions

3. Hyperlipidemia : Abnormally elevated level of lipid in blood, thes e lipids c a n adhe r e t o th e w al l s of th e ar t eri e s a n d restrict blood flow which creates significant risk of heart attack and stroke There are 3 major lipids in our blood Cholesterol Triglycerides Phosp h oli p ids

4. Cholestrol : which is necessary for the synthesis of bile acid . which provides energy to Triglycerides : the cell. Phospholipids : which is the major component of cell membrane .

5. Lipid produces in liver. From liver lipids are not able to move to blood stream because they are insoluble in blood plasma . So, liver w raps protein around the lipid resulting in new molecule called lipoprotein Lipoprotein move to blood stream through out the body

6. Types of lipoprotein : Very low density lipoprotein Low density lipoprotein High density lipoprotein Intermediate density lipoprotein

7. Very low density lipoprotein (VLDL) It composed of low level of protein , & high level of cholesterol & triglyceride Protein cholesterol T ri gl y c erides

8. Low density lipoprotein (LDL) It composed of only protein and cholestrol. It is also known as bad cholestrol. Protein Cholesterol

9. High density lipoprotein (HDL) : It composed of more amount of protein and very less amount of cholestrol. It is also known as good cholestrol Protein Cholestrol T ri gl y c eride

10. Firstly liver releases VLDL in blood stream VLDL provides triglyceride to various cell for function . After utilizing triglyceride VLDL be c omes LDL w hich c o n tai n o n l y Protein and cholestrol. LDL p r o vides cholest r ol t o v arious cell which required .

11. If our body makes too much LDL , i t will de p osi t ed t o th e w alls of ar t e r y causing a fat material called plaque. Due to which narrow blood vessel thereby reduce blood flow , that’s w h y the y a r e calle d ba d chole s t r ol.

12. L i v er also ma k es HD L tha t r em o v es excess of cholestrol from cells and plaque , and returns excess cholestrol to liver that’s why they are called good cholestrol.

13. TC = 140 – 200 mg/dl HDL = 40 – 75 mg/dl LDL = 50 – 130 mg/dl TG = 60 – 150 mg/dl Normal Range

14. Calculation Time

15. TC = HDL + LDL + VLDL VLDL = TG/5 TC = HDL + LDL + (TG/5) Note down this formula

16. VLDL = TG/5 (mg/dl) VLDL = TG/2.2 (mmol/ ltr ) Formula invalid if TG > 400 mg/dl Note this***

17. TG: 230 mg/dl HDL: 30 mg/dl LDL: 195 mg/dl Calculate TC Example 1

18. TG: 230 mg/dl HDL : 30 mg/dl LDL : 195 mg/dl Calculate TC Solution TC = HDL + LDL + VLDL VLDL = TG/5 TC = HDL + LDL + (TG/5) TC = 30 + 195 + (230/5) TC = 30 + 195 + 46 TC = 271 mg/dl

19. TC: 230 mg/dl TG: 120 mg/dl HDL: 25 mg/dl Calculate VLDL and LDL Example 2

20. TC: 230 mg/dl TG: 120 mg/dl HDL: 25 mg/dl Calculate VLDL and LDL Solution Step – 01: VLDL = TG/5 VLDL = 120/5 Step – 02: LDL = TC – (HDL+VLDL) LDL = 230 – (25 + 24) VLDL = 24 mg/dl LDL = 181 mg/dl

21. TC: 260 mg/dl HDL: 45 mg/dl LDL: 145 mg/dl Find TG Example 3

22. TC: 260 mg/dl LDL: 145 mg/dl HDL: 45 mg/dl Calculate TG Solution Step – 01: VLDL = TC – (HDL+LDL) VLDL = 260 – 190 VLDL = 70 Step – 02: VLDL = TG/ 5 TG = VLDL x 5 TG = 70 x 5 TG = 350 mg/dl

23. Management of hyperlipidaemia start with therapeutic life changes (TLC) which includes; a cholesterol-lowering diet (TLC diet), physical activity, quitting smoking (if applicable), weight management, and antihyperlipidemia drugs Management

24. Classification

25. Drug used to lower lipid levels : HMG-CoA reductase inhibitors Bile acid Sequestrants Fibrates Nicotinic acid (Niacin) Cholesterol absorption inhibitors PCSK9 inhibitors

26. HMG COA REDUCTASE INHIBITOR : ATORVASTATIN, FLUVASTATIN, LOVASTATIN PRAVATATIN, R OSU V A S T A TI N , FIBRATES : FENOFI B R A TES GEMFIBROZIL, CLOFIBRATE BILE ACID SEQUESTRANTS INHIBITOR : COLESEVELAM, COLESTIPOL, C H OLE S T YRA MINE NICOTINIC ACID : NIACIN CHOLESTROL ABSORPTION INHIBITOR : EZETIMBE

27. HMG-CoA reductase inhibitors Lovastatin , atorvastatin, Rosuvastatin (5 to 40 mg/day) Mechanism of action: Inhibit the first enzymatic step in cholesterol synthesis . Analogs of HMG (3-hydroxy-3 methylglutaryl-CoA) HMG-CoA reductase catalyzes synthesis of mevalonic acid from HMG-CoA and is the rate limiting step in cholesterol biosynthesis Leads to up-regulation of LDL receptors in liver Simvastatin, lovastatin (prodrugs). Atorvastatin &Rosuvastatin are the most potent.

28. Therapeutic uses: Effective in all types of hyperlipidaemia except those who are homozygous for familial hypercholesterolemia (lack of LDL receptors ). Usually combined with other drugs . Great for all hyperlipidaemias involving increased levels of LDL or cholesterol Atherosclerosis; stroke prevention Primary prevention of CAD

29. Headache Nausea Sleep disturbance Myositis and RHABDOMYOLYSIS , primarily when given with gemfibrozil or Cyclosporine ; myositis is also seen with severe renal insufficiency ( CrCl <30 mL/min). CI in pregnancy Increase in liver enzymes (serum transaminases should be monitored continuously ,CI in hepatic dysfunction ). Cataract and GIT upset. Increase in warfarin levels . (Potentiate)

30. Examples; Cholestyramine (4 to 24 g/day), Cholestipol (5 to 30 g/day), Colesevelam (3.75 g/day ) Used in Hyperlipidaemias involving ISOLATED INCREASES OF LDL Bile acids Sequestrants(resins)

31. Mechanism of action These are anion exchange resins; bind bile acids in the intestine forming complex → Loss of bile acids in the stools → ↑ conversion of cholesterol into bile acids in the liver. Decreased concentration of intrahepatic cholesterol → compensatory increase in LDL receptors → ↑ hepatic uptake of circulating LDL → ↓ serum LDL cholesterol levels .

32. Therapeutic uses : Of choice in treatment of type IIA and IIB hyperlipidaemias (along with statins when response to statins is inadequate or they are contraindicated ). useful for Pruritus in biliary obstruction (↑ bile acids ).

33. Examples ; Gemfibrozil (600 mg BID), Fenofibrate 145 mg/day and 160 to 200 mg/day (Prodrug) T ype III lipoproteinaemia (familial dysbetalipoproteinemia) Hypertriglyceridemia useful for Pruritus in biliary obstruction (↑ bile acids) Fibrates

34. Mechanism of action: Agonists at PPAR ( peroxisome proliferator - activated receptor) → expression of genes responsible for increased activity of plasma lipoprotein lipase enzyme → hydrolysis of VLDL and chylomicrons→ ↓ serum TGs - Increase clearance of LDL by liver & ↑ HDL.

35. Skin rash, Gastrointestinal (nausea, bloating, cramping) Myalgia ; Lowers blood cyclosporine levels; potentially nephrotoxic in cyclosporine treated patients. Avoid in patients with CrCl <30 mL/min. (Fenofibrate) Potentiates warfarin action. Absorption of gemfibrozil diminished by bile acid Sequestrants. (Gemfibrozil) Side effects

36. Nicotinic acid (Niacin) Examples; Niacin (IR: 1 to 6 g/day or XR 0.5 to 2 g/day) The first and cheapest anti- hyperlipidaemic agent. Decrease both TGs (VLDL) and cholesterol (LDL) levels . Therapeutic use: Uses Hyperlipidaemias with very high VLDL and LDL Patients with very low HDL

37. It is a potent inhibitor of lipolysis in adipose tissues → ↓ mobilization of FFAs (major precursor of TGs) to the liver → ↓ VLDL (after few hours ). Since LDL is derived from VLDL so ↓ VLDL → ↓ LDL (after few hours). ↑ HDL level (the most potent). ↓ endothelial dysfunction →↓ thrombosis.

38. dry skin myositis Prostaglandin-mediated cutaneous flushing, warm sensation Headache Pruritus, Nausea, Vomiting, diarrhea hyperpigmentation (particularly in intertriginous regions ) Decreased glucose tolerance Hepatotoxicity (check AST, ALT levels) Rhabdomyolysis Hyperuricemia (inhibits tubular secretion of uric acid) Major side effect and drug interactions

39. Cholesterol absorption inhibitors Examples; Ezetimibe (10 mg/day ) Therapeutic use Used in hypercholesterolemia together with statins & diet regulation Ezetimibe + statins → synergistic effects. Fibrates and statins are CI → myopathy. Nicotinic acid and statins → myopathy.

40. Mechanism of Action: Inhibits intestinal cholesterol absorption → ↓ concentration of intrahepatic cholesterol→ compensatory ↑ in LDL receptors →↑ uptake of circulating LDL →↓ serum LDL cholesterol levels.

41. Side effects Diarrhea Abdominal pain CI liver dysfunction

42. PCSK9 inhibitors Examples; Alirocumab (75 to 150 mg 2/7 w), Evolocumab (140 mg 2/7 w or 420 mg 1/12 m) Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease produced predominantly in the liver that leads to the degradation of hepatocyte LDL receptors and increased LDL-C levels This category of lipid lowering therapy appears promising in a range of clinical situations. They are given subcutaneously The major side effect is injection site reaction

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